Acute Respiratory Distress Syndrome Network, Brower RG, Matthay MA, et al. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med. 2000;342(18):1301-1308
In the early days of mechanical ventilation, the primary aim was to normalize arterial blood gases. Little was known about the potential deleterious effects of positive pressure ventilation on the lung that could add insult to injury. Back in the 1990s, a tidal volume of 10–15 ml/kg was often employed to ensure adequate gas exchange (1). Respiratory acidosis was considered detrimental; higher tidal volumes were often employed to target arterial pH levels. Animal studies had shown that high tidal volume ventilation was associated with the release of inflammatory mediators, culminating in damage to the alveolar epithelium and the capillary endothelium, leading to atelectasis and worsening hypoxemia (2). Furthermore, the release of inflammatory mediators from the lung could culminate in multiorgan dysfunction (2). While the use of lower tidal volumes appeared to offer putative benefits through lung protection and amelioration of the inflammatory response, this strategy carried the potential for harm from hypercapnia and acidemia. The evidence from early studies on animal models and clinical trials that followed were conflicting.
Nearly half a century ago, Webb and Tierney demonstrated in a rat model that ventilation with high positive pressures of 45 cm H2O and zero PEEP led to rapid development of alveolar and perivascular edema, severe hypoxia, and decreased lung compliance. The application of a PEEP of 10 cm H2O protected against high-inspiratory pressure-related lung injury (3). In an observational study, Hickling et al., using a lung-protective strategy of low tidal volumes between 4–7 ml/kg and limiting the peak inspiratory pressure to 30–40 cm of H2O, demonstrated lower mortality than predicted by the APACHE II score (4).
Amato et al. randomly assigned patients with early acute respiratory distress syndrome (ARDS) to a conventional or lung-protective ventilation strategy (5). The conventional strategy included using tidal volumes of 12 ml/kg, the lowest level of PEEP to maintain oxygenation and normal carbon dioxide levels; the lung-protective strategy involved the application of PEEP above the lower inflection point on the static pressure-volume curve, tidal volumes of <6 ml/kg and driving pressures of <20 cm H2O, allowing permissive hypercapnia. The lung-protective strategy was associated with improved 28-day survival, more rapid weaning from mechanical ventilation, and less barotrauma. However, contrasting findings emerged from other randomized controlled trials (RCTs).
Brochard et al. compared a tidal volume of 10 ml/kg, limiting plateau pressure to 25 cm H2O, compared with tidal volumes of >10 ml/kg, aiming for normal PCO2. A low tidal volume, limited Pplat strategy did not lead to improved survival, duration of mechanical ventilation, barotrauma, or multiorgan failure (6). These findings were echoed by another RCT that compared tidal volumes of <8 ml/kg compared with 10–15 ml/kg in patients at high risk of ARDS (7). Yet another study compared a lung-protective (tidal volume of 5–8 ml/kg ideal body weight, plateau pressure of < 30 cm H2O) vs. conventional strategy (tidal volume of 10–12 ml/kg ideal body weight, plateau pressure of <55 cm H2O). Although a lung-protective strategy was found to be safe, there was no significant difference in important clinical outcomes, including the duration of ventilation or mortality (8).
The use of low tidal volumes offered potential clinical benefit by reducing injurious lung stretch. Considering the lack of robust evidence from available studies, the Acute Respiratory Distress Syndrome Network (ARDSNet) group of the National Heart, Lung, and Blood Institute in the US conceived an RCT that compared lower with traditional, high tidal volumes among patients with ARDS (9).
Population and design
The ARDSNet trial was conducted between March 1996 to March 1999 and enrolled patients from 10 university centers of the network. The study enrolled adult patients with ARDS who underwent invasive mechanical ventilation, with a PaO2/FiO2 ratio of ≤300 mm Hg, bilateral infiltrates on the chest radiograph with no clinical evidence of left atrial hypertension, and a pulmonary artery wedge pressure, if measured, of ≤18 mm Hg. Enrolment in the study was based on the American-European Consensus Conference definitions of ARDS (10).
Patients were excluded if more than 36 hours had elapsed after meeting the ARDS criteria. Patients with intracranial hypertension, neuromuscular disease, severe chronic respiratory disease, burns of >30% of body-surface area, and a body weight of > 1 kg/cm of height were also excluded. Other exclusion criteria were the presence of chronic liver disease, and those who had undergone bone marrow or lung transplantation.
Ventilation strategy in both groups
Patients were ventilated in the volume-assist-control mode until weaning or for 28 days post-randomization. The predicted body weight was calculated as follows.
Male patients: 50 + 2.3 [height in inches – 60]
Female patients: 45.5 + 2.3 [height in inches – 60]
Traditional tidal volume group
The initial tidal volume was set at 12 ml/kg of predicted body weight. The tidal volume was reduced by 1 ml/kg in a stepwise manner to maintain the plateau pressure (Pplat) ≤ 50 cm H2O, down to a minimum tidal volume was 4 ml/kg. If the Pplat was <45 cm H2O, the tidal volume was increased by 1 ml/kg at a time for a minimum Pplat of 45 cm H2O. The maximum tidal volume used was 12 ml/kg. Thus, the Pplat was maintained between 45–50 cm H2O, for a maximum tidal volume of 12 ml/kg.
Low tidal volume group
The initial tidal volume was set at 6 ml/kg of predicted body weight. If the Pplat exceeded 30 cm H2O, the tidal volume was reduced by 1 ml/kg at a time to maintain the Pplat below this level. If the Pplat was <25 cm H2O, the tidal volume was increased in steps of 1 ml/kg until the Pplat rose to this level. The tidal volume could be increased to 7–8 ml/kg if considered appropriate, provided the Pplat remained ≤30 cm H2O. The Pplat in this group was maintained between 25–30 cm H2O.
The tidal volume was not allowed to drop below 4 ml/kg in either group. The Pplat limit of 30 cm H2O in the low tidal volume group and 50 cm H2O in the conventional tidal volume group could be exceeded to achieve a minimum tidal volume of 4 ml/kg, and an arterial pH of not less than 7.15. Other ventilation procedures including the weaning protocol were similar in both groups. If a patient required reinstitution of mechanical ventilation after being weaned off within the 28-day period, the same tidal volume protocol was followed.
Sample size calculation
Four interim analyses were planned after the recruitment of 200, 400, 600, and 800 patients. The trial was designed to detect a 10% difference in mortality in the low tidal volume group (from 50 to 40%) with 87% power at a two-sided significance level.
The trial was stopped after the fourth planned interim analysis after the enrollment of 861 patients. At this stage, the low tidal volume strategy was found to be more efficacious compared with the use of traditional tidal volumes. Baseline characteristics were similar in both groups, except for higher minute ventilation in the low tidal volume group.
The tidal volume and Pplat were significantly lower on days 1, 3, and 7 in the low tidal volume group. There was a clear difference in the tidal volume between the two groups. The mean tidal volume on days 1–3 was 6.2± 0.8 ml/kg in the low tidal volume group compared with 11.8±0.8 ml/kg in the traditional tidal volume group. The mean Pplat levels were also significantly lower in the low tidal volume group (25±6 vs. 33±8 cm H2O). In the low tidal volume group, the PaCO2 levels were significantly higher on days 1,3, and 7; the arterial pH was significantly lower on days 1 and 3. The PaO2/FiO2 ratio was lower in the low tidal volume group on days 1 and 3.
The first primary outcome, death before hospital discharge and before being able to breathe without assistance was significantly less in the low tidal volume group (31.0% vs. 39.8%, p = 0.007). The second primary outcome, the ability to breathe without assistance by day 28, was significantly higher in the low tidal volume group (65.7% vs. 55.0%, p < 0.001).
Among the other outcomes, the number of ventilator-free days at 28 days was higher in the low tidal volume group (mean of 12 vs. 10 days). The number of days without non-pulmonary organ failure was also higher in the low tidal volume group. Specifically, the incidence of circulatory failure, renal failure, and coagulation failure was lower in the low tidal volume group. The incidence of barotrauma was similar in both groups. There was no significant difference in the use of neuromuscular blockers and sedatives between the two groups. On day 3, the decrease in the plasma interleukin-6 levels was greater in the low tidal volume group, suggesting a reduced inflammatory response. Table 1 represents the main trial outcomes.
Table 1. Main trial outcomes
|Outcome||Low tidal volume||Traditional tidal volume||p-value|
|Death before discharge and before being able to breathe without assistance||31%||39.8%||0.007|
|Ability to breathe without assistance at day 28||65.7%||55%||<0.001|
|Ventilator free days from day 1 to day 28||12 ± 11 days||10 ± 11 days||0.007|
|Barotrauma from day 1 to day 28||10%||11%||0.43|
|Non-pulmonary organ failure-free days from day 1 to day 28||15 ± 11 days||12 ± 11 days||0.006|
The authors concluded that in patients with ARDS, mechanical ventilation with lower compared to traditionally used tidal volumes reduced mortality and the duration of mechanical ventilation. They suggested that prevention of lung stretch by reducing tidal volumes is a key strategy during mechanical ventilation in patients with ARDS.
The results of the ARDSNet trial provided important insights into improving outcomes in patients with ARDS on mechanical ventilation. The trial design and methodology were robust and appropriate to address the comparison between low and higher tidal volumes and their impact on clinical outcomes. The trial was conducted across multiple centers in the US, providing external validity. The large sample size provided adequate power to identify a difference between groups in the primary outcome. Interim analyses were performed meticulously, and the trial was ceased when the results favored the low tidal volume group. The investigators evaluated clinically relevant, objective outcomes, including mortality and the duration of ventilation.
In the traditional tidal volume group, patients may have been exposed to relatively high tidal volumes compared to the usual practice of the study period. The Pplat levels were also correspondingly higher compared to conventional practice. The mean tidal volume employed at baseline was approximately 10 ml/kg; this essentially meant that the tidal volume was increased in most patients in the traditional group to comply with the study protocol.
The authors did not provide information on the immediate cause of death; it is plausible that mortality may have been due to extra-pulmonary organ failure, and not primarily due to a lung-protective effect from the use of low tidal volumes.
Was a low tidal volume strategy associated with a more favorable hemodynamic status, and hence, improved outcomes? No information was available on the cardiovascular status or the use of vasopressors.
The study allowed the non-standardized use of intravenous sodium bicarbonate to combat hypercapnic acidosis. The authors contend that the buffering effect may have contributed to improved outcomes among hypercapnic patients in the low tidal volume group. This assertion is in contrast to available evidence suggesting that hypercapnia may not be harmful, and indeed, may have beneficial effects (11).
In the traditional tidal volume group, the Pplat was maintained between 45–50 cm H2O; this is considerably higher than the recommendations in vogue during the study period (12). Besides, in earlier studies that compared low vs. high tidal volumes that did not show a difference in outcomes, the mean Pplat levels in the higher tidal volume groups were much lower, at 29±7 (7) and 31±9 cm H2O (6).
Although more than 6,000 patients were screened, 2,587 were considered ineligible due to technical reasons, although they had met the enrollment criteria. These patients received usual care; however, the mortality in this cohort was similar to the mortality of the low tidal volume group (31.7% vs. 31%). This finding suggests that conventional care was compared with higher than usual tidal volumes in the trial, and could perhaps have contributed to increased mortality (13).
Would tidal volume-related outcomes depend on lung compliance? Among patients with low lung compliance, higher tidal volumes appear to have increased mortality; in contrast, in patients with higher lung compliance, a higher tidal volume was associated with lower mortality (13). This observation is particularly relevant considering the wide variability of lung involvement and compliance in ARDS. Anatomic studies have also revealed a poor correlation between the ideal body weight and the extent of lung involvement in ARDS (14).
Driving pressure vs. tidal volumes
Is driving pressure (ΔP, Pplat – PEEP) an important determinant of survival in patients with ARDS who are mechanically ventilated? Amato et al. performed a multi-level mediation analysis of data from 3562 patients with ARDS from nine RCTs to answer this question (15). They observed that ΔP was the most robust predictor of survival, even among patients who were being ventilated using a lung-protective strategy with low tidal volumes and Pplat. The tidal volume or PEEP levels were not independently associated with survival; low tidal volumes were associated with improved survival only if it resulted in a reduction in the ΔP.
The ARDSNet trial addressed an important, albeit contentious clinical question of the time by evaluating a lung-protective ventilation strategy that had been studied in previous clinical trials with no definitive answers. The trial focused on testing a lung protective ventilation strategy, which involved using lower tidal volumes and lower airway pressures. The investigators compared a low tidal volume of 6 ml/kg of predicted body weight compared to a more traditional tidal volume of 12 ml/kg. They observed improved survival and more ventilator-free days with the low tidal volume, lung-protective ventilation strategy. Although there were criticisms related to the use of a fixed tidal volume and a “one-size fits all” strategy, the findings appeared robust and applicable to a heterogeneous patient population with ARDS. This approach has since become the standard of care in managing patients with ARDS, as it has been shown to reduce ventilator-induced lung injury. The findings of this pivotal trial had a profound influence on the management of ARDS. It was widely accepted by the critical care fraternity leading to perceptible changes in clinical practice, with the use of low tidal volumes as part of a lung-protective ventilation strategy.
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